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Monthly Archives: March 2012

As anyone who’s ever taken an Alcohol Edu course (or been 21 in the last decade) knows, consuming too much alcohol can cause memory loss, colloquially known as a “blackout”. This anterograde amnesia stems from an inability of the brain to form new long-term memories and is caused by a disruption in the GABA and NMDA receptors in the prefrontal cortex (PFC) and medial temporal lobes when drinking.

First, for those of you who skipped (or drank) your way through your alcohol education, a brief reminder on the effects of alcohol on the brain. GABA is a primary inhibitory neurotransmitter, acting to decrease the likelihood of a cell’s firing. Alcohol acts as a GABA agonist, elevating levels throughout the brain and therefore diminishing the rates of firing in normal cellular processes. At high levels, alcohol also acts upon glutamate NMDA receptors, one of the main excitatory neurotransmitter systems. Alcohol works as an NMDA antagonist, blocking the NMDA receptors and preventing glutamatergic activation, further inhibiting neuronal functioning. This inhibition particularly occurs in the PFC, medial temporal cortex and the parietal lobe, primary targets of alcohol in the brain. In the hippocampus in particular, an area in the medial temporal cortex crucial to memory formation, this inhibition can result in a disruption of long-term potentiation, a cellular process involved in the consolidation of short-term to long-term memories.

Alcohol’s effect on the PFC also impacts memory ability, as short-term memories are maintained there while they are being worked on or rehearsed. However, when attention shifts to a new stimulus this memory must be consolidated into a more stable long-term version via cellular activity in the hippocampus, or else it will be discarded and forgotten. Alcohol’s inhibition of the PFC via its effects on GABA and glutamate can disrupt the maintenance of these short-term memories, decreasing the likelihood of consolidation and preservation. The dampening of firing in the PFC is also attributed to the behavioral disinhibition that so commonly succeeds alcohol consumption, as the PFC can no longer inhibit or control impulses as well.

Now, on to the exciting bit! In individuals who regularly experience alcohol-induced memory loss, or a blackout, it is the contextual memory that seems to be most impaired. This refers to the details surrounding an experience, such as where, when and with whom the event occurred. However, blackouts seem to affect some drinkers more than others, and are not necessarily determined by the amount of alcohol that an individual consumes. Simply put, you either blackout when drinking large amounts of alcohol or you do not.

Published online this week in Alcoholism: Clinical and ExperimentalResearch, psychologists from the University of California, San Diego and the University of Texas, Austin have recently confirmed this urban drinking legend by testing 24 regular binge drinkers, 12 of whom admitted to blacking out on a regular basis, reporting on average two blackouts per month, and 12 who drank comparable amounts of alcohol but declared no memory problems when drinking. Both groups were matched on their typical alcohol consumption, averaging 3 drinking days per week and consuming 4-5 drinks at a time on a typical day when drinking. Both groups also had comparable binge tendencies, consuming 10 or more drinks on occasion over the previous 3 months.

Participants were tested on a contextual memory task using functional magnetic resonance imaging (fMRI) both when sober and after drinking to a blood alcohol content of .08, the legal limit in the United States, typically 3 drinks for a male and 2 for females. During both the sober and intoxicated trials, participants performed equally well in their behavioral scores, recalling similar amounts of information regardless of their blackout group status. Groups also did not differ in their response times on the task during either condition, however both groups recalled significantly fewer trials when intoxicated and were significantly slower than when sober.

In the imaging analysis, there were no differences in activation levels between the groups during either encoding or retrieval for the sober condition of the task. However, when intoxicated, both groups demonstrated significantly less activation in the right frontopolar PFC during retrieval. The blackout group also had significantly less activation during both the encoding and recall portions of the experiment after consuming moderate amounts of alcohol as compared to the non-blackout group. Specifically, participants with a history of blacking out showed less activation in the left frontopolar PFC during encoding, and decreased activity in the right posterior parietal cortex and the bilateral dorsolateral PFC during retrieval as compared to their non-blackout contemporaries. This fronto-parietal network is implicated in attentional maintenance and inhibition, as well as working memory and executive control, suggesting that there could be greater difficulties in these skills in the blackout group when drinking.

The researchers speculate that the decrease in activity in the frontal pole during intoxication is indicative of an alcohol-induced impairment in executive functioning in both groups, particularly in regards to working memory and cognitive maintenance. The additional decrease in activation in the fronto-parietal network seen in the blackout group also suggests a greater disability in executive functioning and memory maintenance in these individuals when drinking. However, it is notable that there were not any significant behavioral differences between the two groups in total memory recall, particularly during the intoxication condition.

While it is reassuring that there were no impairments in either group during the sober condition, the drinking results do seem to suggest that there may be underlying problems with memory and executive functioning in those individuals with a proclivity for forgetting, which could emerge after more chronic drinking behaviors. Why some people are predisposed towards these additional memory impairments is still unclear, but there does seem to be something different in the brains of those who blackout regularly that is not just dependent on the amount of alcohol they drink.

I recently attended a fascinating lecture by Cambridge neuroscientist Robin Franklin on progenitor cells (“neural stem cells”) and their treatment potential in neurodegenerative diseases, such as multiple sclerosis (MS). The progressive form of MS, which follows from the relapsing-remitting version, stems from a decreasing ability of oligodendrocyte cells and their crucial myelin sheaths to be regenerated after they are destroyed through the course of the disease. Dr. Franklin’s lab studies cell remyelination, specifically focusing on oligodendrocyte precursor cells (OPCs), which are a form of progenitor that can evolve into oligodendrocytes to replace the damaged cells and sheaths. However, as an individual ages, these cells have a greater difficulty differentiating and do not regenerate as efficiently, which is most likely the cause in the transition to the progressive form of the disease. Dr. Franklin’s lab has used parabiosis to study the effects of aging on progenitor cell differentiation, the amazing science fiction-esque research method of fusing two mice together (in this case young and old), enabling them to share blood flow. From this research, Dr. Franklin has provided the most compelling evidence to date that decreases in crucial blood proteins as an individual ages are behind the increasing disability in remyelination and disease progression.

But let’s take a step back and do some defining, as I’ve just introduced a lot of jargon in that first section. Until only the last few decades, it was commonly thought that brain structure was relatively stable through adulthood, the window of neurogeneration and plasticity closing after adolescence. However this myth has been debunked, and there has been a revival in research on neural plasticity in adulthood and its potential treatment implications for individuals suffering from stroke, traumatic brain injury, and neurodegenerative diseases.

Multiple sclerosis (MS) is a neurodegenerative disease that consists of the breakdown of myelin sheaths, the protective coatings that surround cell axons and make up white matter tracts, enabling more efficient signal transmission between cells. This is in contrast to other neurodegenerative diseases, such as Huntington’s or Parkinson’s disease, which stem from the death of gray matter neurons themselves. These myelin sheaths originate from oligodendrocyte cells, bizarre looking neurons that consist of a cell body and up to 80 projections of giant wrap-around sheaths coming out of each arm. These sheaths encase and protect neighboring cell axons, however in MS both the sheaths and the oligodendrocyte cells become damaged, eventually breaking apart and dying.

Fortunately, the brain contains its own version of stem cells, early stage neurons called progenitor cells that have the potential to develop into a variety of different types of mature neurons. These progenitor cells are particularly adept at evolving into oligodendrocytes, and thus in the early stages of MS these lost cells can be replaced relatively easily. This depletion-repletion process explains the relapsing-remitting course of the early stages of MS. However, as the disease progresses it becomes increasingly difficult for these oligodendrocytes to regenerate, stemming from an increasing inefficiency in differentiation of the progenitor cells. This turn of events seems to define the later stage of progressive MS, though why this decline occurs has been unclear.

Enter Dr. Franklin and his team of researchers. Published recently in Cell Stem Cell, Dr. Franklin’s group used parabiosis to determine that the decreasing efficiency of cell regeneration was caused by an increase in age. Comparing heterochronic (young and old mice joined together) with isochronic (young-to-young or old-to-old) pairs, researchers damaged the myelin in the spinal cord of the older animals using a local toxin injection, and measured subsequent levels of both oligodendrocyte precursor cells (OPCs) and oligodendrocytes themselves. After 14 days, the levels of OPCs in the older damaged mice in the heterochronic pairs was significantly greater than those in the older isochronic animals, and at 21 days the levels of mature oligodendrocytes in old heterochronic animals were equivalent to those in young isochronic pairs. Both of these results were associated with an overall increase in myelination in the damaged heterochronic-old animals as compared to the isochronic-old pairs.

This improvement in regeneration seems to stem from an increase in differentiation of the already existing progenitors in the old mice, rather than a pilfering of these cells from their young counterparts. Instead, by joining together the vascular systems of the young and old animals, the older mice were able to benefit from increased levels of proteins and cells, such as macrophages, that signal the need for differentiation in the progenitors, enabling them to once again trigger the transformation process into full-fledged oligodendrocytes.

In his talk, Dr. Franklin was quick to point out that this was not a therapeutic study, but that it instead shows a pharmacological approach towards regeneration of oligodendrocytes for remyelination in MS may be promising going forward. These results suggest that it is not an influx of new progenitor cells that is needed in older individuals, but instead an enhancement of the signalling cells that make these transformations possible. This would of course be a far easier clinical undertaking than surgically fusing together young and old patients, and provides one of the first bits of evidence for treatment options in actually repairing the damage caused by neurodegenerative diseases.